RESUMO
Paraneoplastic syndrome is a broad spectrum of signs and symptoms due to neoplasm, attributed to substances produced by tumor cells, or in response to it. Myasthenia gravis (MG) is a well-known paraneoplastic neurological syndrome (PNS), frequently associated with thymic abnormalities, but rarely reported in patients with lymphoplasmacytic lymphoma.This study presents the case of a 52-year-old Indonesian male patient who was diagnosed with Waldenstrom macroglobulinemia (WM), a rare B-cell neoplasm, after developing a new onset of MG with myasthenic crisis. the patient's MG features improved with Ibrutinib as a treatment targeted toward cancer. This is the first case report presenting the treatment response of Ibrutinib in WM with myasthenic crisis. The literature was reviewed to explain the possibility of MG as a paraneoplastic syndrome of WM and the treatment response of Ibrutinib for this patient, as well as summarizing previous case reports of concomitant MG and WM.MG should be considered a paraneoplastic malignancy syndrome, including WM, during diagnostic workup. Ibrutinib should also be considered when available to patients, due to its adequate response in both previously treated and treatment naïve patients.
Assuntos
Adenina , Miastenia Gravis , Piperidinas , Pirazóis , Pirimidinas , Macroglobulinemia de Waldenstrom , Humanos , Macroglobulinemia de Waldenstrom/tratamento farmacológico , Macroglobulinemia de Waldenstrom/complicações , Masculino , Adenina/análogos & derivados , Adenina/uso terapêutico , Pessoa de Meia-Idade , Piperidinas/uso terapêutico , Miastenia Gravis/tratamento farmacológico , Miastenia Gravis/complicações , Miastenia Gravis/diagnóstico , Pirimidinas/uso terapêutico , Pirazóis/uso terapêutico , Síndromes Paraneoplásicas do Sistema Nervoso/tratamento farmacológico , Síndromes Paraneoplásicas do Sistema Nervoso/etiologia , Resultado do TratamentoRESUMO
PURPOSE OF REVIEW: Waldenström macroglobulinemia is a rare non-Hodgkin lymphoma (NHL) characterized by lymphoplasmacytic bone marrow infiltration associated with an immunoglobulin M (IgM) monoclonal gammopathy. Over the past two decades, a number of important novel therapies have emerged for the treatment of relapsed and refractory (R/R) WM. The purpose of this review is to discuss these novel agents. RECENT FINDINGS: Chemoimmunotherapy which formed the basis treatment for R/R WM is slowly being replaced by novel targeted agents. These therapies, including Bruton's tyrosine kinase inhibitors, proteasome inhibitors, and B-cell lymphoma 2 inhibitors, have widened the landscape of management. Emerging therapies currently under investigation, such as bispecific T-cell engagers, chimeric antigen T-cell receptor therapy, and novel small molecule inhibitors, have additionally shown the potential to improve response and survival. The treatment of R/R WM has greatly evolved, in large part due to a greater understanding of the biology of WM, and the evaluation of novel targeted agents in the basket trials of NHL, showing early activity in the small WM cohorts. Combination regimens with these established and emerging novel therapies have the potential to further improve disease control and induce higher rates of deep responses. Strategies aimed at altering the disease trajectory would require randomized controlled trials to provide relevant data on optimal integration and sequencing of more effective and tolerable regimens earlier in the disease course.
Assuntos
Macroglobulinemia de Waldenstrom , Macroglobulinemia de Waldenstrom/tratamento farmacológico , Macroglobulinemia de Waldenstrom/terapia , Humanos , Gerenciamento Clínico , Recidiva , Terapia de Alvo Molecular/métodos , Resistencia a Medicamentos Antineoplásicos , Inibidores de Proteínas Quinases/uso terapêutico , Imunoterapia/métodos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêuticoRESUMO
BACKGROUND: Waldenström's macroglobulinemia (WM) is defined as a lymphoplasmacytic lymphoma (LPL) involving the bone marrow (BM) with presence of IgM monoclonal protein, and comprises > 95% of all LPL cases. Rituximab-based regimens have been predominant in the management of WM. Infusion-related reactions (IRRs) are a primary concern with rituximab, although it is generally better tolerated with less toxicity than conventional anticancer agents. Here, we present an autopsy case of an elderly man who died suddenly after receiving the initial infusion of rituximab for WM/LPL. CASE PRESENTATION: An 84-year-old man was found dead in his bedroom. He had undergone the initial intravenous rituximab infusion for progressive anemia related to Waldenström's macroglobulinemia/lymphoplasmacytic lymphoma (WM/LPL) approximately 15 h before death. Although the protocol for rituximab administration and additional medication was considered appropriate, he exhibited several symptoms consistent with infusion-related reactions (IRRs) during the infusion. Autopsy revealed monotonous proliferation of small-to-medium-sized lymphocytic cells in the bone marrow, consistent with the premortem diagnosis of WM/LPL. Additionally, immunoglobulin λ-light chain-derived amyloid (ALλ) deposition was identified in all organs other than the brain. Although ALλ deposition and LPL infiltration were found in the heart, they were not severe enough to cause severe functional impairment. Severe congestion and/or edema were observed in the lungs, liver, and brain. Although significant inflammatory cell infiltration was not found in any organs, laboratory tests revealed elevated serum levels of inflammatory cytokines, including interleukin-1ß, interleukin-6, tumor necrosis factor-α and the presence of IgM-λ monoclonal protein. CONCLUSION: Acute IRRs associated with the initial rituximab infusion were the major contributing factor to his sudden unexpected death. The autopsy findings of present case suggest the necessity for thorough monitoring of older patients with WM/LPL undergoing rituximab treatment, particularly when pronounced IRRs occur during the first administration, in addition to investigating complications of WM/LPL before infusion.
Assuntos
Autopsia , Rituximab , Macroglobulinemia de Waldenstrom , Humanos , Macroglobulinemia de Waldenstrom/tratamento farmacológico , Macroglobulinemia de Waldenstrom/patologia , Macroglobulinemia de Waldenstrom/complicações , Rituximab/efeitos adversos , Rituximab/administração & dosagem , Masculino , Idoso de 80 Anos ou mais , Morte Súbita/etiologia , Antineoplásicos Imunológicos/efeitos adversos , Antineoplásicos Imunológicos/administração & dosagem , Medula Óssea/patologia , Evolução Fatal , Infusões IntravenosasRESUMO
Bruton tyrosine kinase (BTK) inhibitors have become a standard of care in the treatment of patients with Waldenström macroglobulinemia (WM) and are the only medications approved by the FDA to treat these patients. As more patients with WM are treated with BTK inhibitors in the United States and worldwide, it is essential to optimize this therapy by selecting the patients who are more likely to benefit from it, and by managing the unique adverse effects associated with these agents. Herein, we propose a genomic-driven approach to selecting patients with WM who are more likely to experience fast, deep, and durable responses to BTK inhibitors, and provide practical strategies for managing adverse effects, including BTK inhibitor dose reductions, switching to other BTK inhibitors, and abandoning BTK inhibitor therapy. Ongoing clinical trials are evaluating covalent and noncovalent BTK inhibitors alone and in combination, as well as BTK degraders, with exciting results, making the horizon for BTK-targeting therapies in WM bright and hopeful.
Assuntos
Tirosina Quinase da Agamaglobulinemia , Inibidores de Proteínas Quinases , Macroglobulinemia de Waldenstrom , Macroglobulinemia de Waldenstrom/tratamento farmacológico , Macroglobulinemia de Waldenstrom/genética , Macroglobulinemia de Waldenstrom/diagnóstico , Humanos , Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/efeitos adversos , Terapia de Alvo Molecular/métodosRESUMO
Objective: To conduct a nationwide physician survey to better understand clinicians' disease awareness, treatment patterns, and experience of Waldenström macroglobulinemia (WM) in China. Methods: This cross-sectional study was conducted from February 2022 to July 2022 by recruiting clinicians with WM treatment experience from hematology, hematology-oncology, and oncology departments throughout China. Quantitative surveys were designed based on the qualitative interviews. Results: The study included 415 clinicians from 219 hospitals spread across thirty-three cities and twenty-two provinces. As for diagnosis, the laboratory tests prescribed by physicians for suspected WM patients were relatively consistent (92% -99% recommendation for laboratory, 79% -95% recommendation for pathology, 96% recommendation for gene testing, and 63% -83% recommendation for imaging examination). However, from a physician's perspective, there was 22% misdiagnosis occurred in clinical practice. The rate of misdiagnosis was higher in lower-level hospitals than in tertiary grade A hospitals (29% vs 21%, P<0.001). The main reasons for misdiagnosis were that WM was easily confused with other diseases, and physicians lacked the necessary knowledge to make an accurate diagnosis. In terms of gene testing in clinical practice, 96% of participating physicians believed that WM patients would require gene testing for MYD88 and CXCR4 mutations because the results of gene testing would aid in confirming diagnosis and treatment options. In terms of treatment, 55% of physicians thought that the most important goal was to achieve remission, while 54% and 51% of physicians wanted to improve laboratory and/or examination results and extend overall survival time, respectively. Among patients with treatment indications, physicians estimated that approximately 21% of them refused to receive treatment, mainly owing to a lack of affordable care and disease awareness. When selecting the most appropriate treatment regimens, physicians would consider patient affordability (63% ), comorbidity (61% ), and risk level (54% ). Regimens containing Bruton tyrosine kinase inhibitor (BTKi) were most widely recommended for both treatment-naïve and relapsed/refractory patients (94% for all patients, 95% for treatment-naïve patients, and 75% for relapsed/refractory patients), and most physicians recommended Ibrutinib (84% ). For those patients who received treatment, physicians reported that approximately 23% of patients did not comply with the treatment regimen due to a lack of affordability and disease awareness. Furthermore, 66% of physicians believe that in the future, increasing disease awareness and improving diagnosis rates is critical. Conclusions: This study is the first national physician survey of WM conducted in China. It systematically describes the issues that exist in WM diagnosis and treatment in China, such as a high rate of misdiagnosis, limited access to gene testing and new drugs, and poor patient adherence to treatment. Chinese doctors believe that improving doctors' and patients' understanding of WM is one of the most urgent issues that must be addressed right now.
Assuntos
Macroglobulinemia de Waldenstrom , Humanos , Macroglobulinemia de Waldenstrom/terapia , Macroglobulinemia de Waldenstrom/tratamento farmacológico , Estudos Transversais , Inibidores de Proteínas Quinases/uso terapêutico , Transdução de Sinais , Inquéritos e Questionários , Fator 88 de Diferenciação Mieloide/genéticaRESUMO
BACKGROUND: Renal injury related to Waldenström macroglobulinemia (WM) occurs in approximately 3% of patients. Kidney biopsy is crucial to discriminate between distinct histopathological entities such as glomerular (amyloidotic and non-amyloidotic), tubulo-interstitial and non-paraprotein mediated renal damage. In this context, disease characterization, management, relationship between renal, and hematological response have been poorly explored. We collected clinical, genetic and laboratory data of seven cases of biopsy-proven renal involvement by WM managed at our academic center and focused on three cases we judged paradigmatic discussing their histopathological patterns, clinical features, and therapeutic options. CASE: In this illustrative case series, we confirm that serum creatinine levels and 24 h proteinuria are parameters that when altered should prompt the clinical suspicion of WM-related renal involvement, even if at present there are not precise cut-off levels recommending the execution of a renal biopsy. In our series AL Amyloidosis (n = 3/7) and tubulo-interstitial infiltration by lymphoma cells (n = 3/7) were the two more represented entities. BTKi did not seem to improve renal function (Case 1), while bortezomib-based regimens demonstrated a beneficial activity on the hematological and organ response, even when used as second-line therapy after chemoimmunotherapy (Case 3) and also with coexistence of anti-MAG neuropathy (Case 2). In case of poor response to bortezomib, standard chemoimmunotherapy (CIT), such as rituximab-bendamustine, represents an effective option (Case 1, 6, and 7). In our series, CIT generates durable responses more frequently in cases with amyloidogenic renal damage (Case 1, 5, and 7). CONCLUSION: In this illustrative case series, we confirm that serum creatinine levels and 24 h proteinuria are parameters that when altered should prompt the clinical suspicion of WM-related renal involvement, even if at present there are not precise cut-off levels recommending the execution of a renal biopsy. Studies with higher numerosity are needed to better clarify the pathological and clinical features of renal involvement during WM and to determine the potential benefit of different therapeutic regimens according to the histopathological subtypes.
Assuntos
Macroglobulinemia de Waldenstrom , Humanos , Macroglobulinemia de Waldenstrom/diagnóstico , Macroglobulinemia de Waldenstrom/patologia , Macroglobulinemia de Waldenstrom/complicações , Macroglobulinemia de Waldenstrom/tratamento farmacológico , Masculino , Idoso , Feminino , Pessoa de Meia-Idade , Rim/patologia , Biópsia , Bortezomib/administração & dosagem , Bortezomib/uso terapêuticoRESUMO
Ibrutinib is a first-in-class Bruton kinase inhibitor against B-cell neoplasms including Waldenström macroglobulinemia (WM). This study evaluated the efficacy and safety of ibrutinib-rituximab in Japanese patients with WM. Patients received ibrutinib 420 mg orally once daily plus weekly rituximab 375 mg/m2 IV (8 infusions total). The primary end point was major response rate (MRR; PR or better) by Independent Review Committee assessment. Secondary endpoints were progression-free survival (PFS), safety, pharmacokinetics, and biomarkers. Primary analysis was conducted in 16 patients [baseline, treatment naïve: 8 (50.0%); relapsed/refractory WM: 8 (50.0%)] who received ibrutinib-rituximab, after all patients completed Week 57 or end of treatment. At primary analysis, MRR was 87.5% [14/16 patients; 95% CI: 61.7, 98.4%; p < 0.0001 (null hypothesis: 32% response rate)]. At final analysis (median study intervention duration: 34.4 months, median follow-up: 35.0 months), MRR was unchanged at 87.5%, but VGPR [6/16 (37.5%)] and PR [8/16 (50.0%)] improved. Prior treatment status did not affect response. At final analysis, median PFS was not reached [36-month PFS rate: 86% (95% CI: 55, 96%)]. No critical safety signals were reported. This study demonstrated a positive benefit/risk profile of ibrutinib-rituximab in Japanese patients with WM, consistent with the iNNOVATE study.
Assuntos
Adenina , Protocolos de Quimioterapia Combinada Antineoplásica , Piperidinas , Rituximab , Macroglobulinemia de Waldenstrom , Humanos , Macroglobulinemia de Waldenstrom/tratamento farmacológico , Macroglobulinemia de Waldenstrom/mortalidade , Adenina/análogos & derivados , Adenina/administração & dosagem , Piperidinas/administração & dosagem , Piperidinas/uso terapêutico , Rituximab/administração & dosagem , Rituximab/efeitos adversos , Rituximab/uso terapêutico , Idoso , Pessoa de Meia-Idade , Masculino , Feminino , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Japão , Pirazóis/administração & dosagem , Pirazóis/uso terapêutico , Pirazóis/efeitos adversos , Pirimidinas/administração & dosagem , Pirimidinas/uso terapêutico , Pirimidinas/efeitos adversos , Idoso de 80 Anos ou mais , Resultado do Tratamento , Povo Asiático , População do Leste AsiáticoRESUMO
Clinical management of Waldenström's Macroglobulinemia has seen major progress in the recent years, triggered by our improved understanding of the biology of the disease and the development of new therapies. Based on this there are multiple treatment options available for patients with WM ranging from classical immunochemotherapy to targeted approaches blocking key enzymes involved in lymphoma growth. This review summarizes our current knowledge about diagnostics and treatment of this rare but recurrent lymphoma subtype, which often presents a major clinical challenge in daily clinical life.
Assuntos
Linfoma , Macroglobulinemia de Waldenstrom , Humanos , Macroglobulinemia de Waldenstrom/diagnóstico , Macroglobulinemia de Waldenstrom/tratamento farmacológico , Recidiva Local de NeoplasiaRESUMO
PURPOSE OF REVIEW: The treatment of Waldenström macroglobulinemia (WM) has evolved over the past decade. With the seminal discoveries of MYD88 and CXCR warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) mutations in WM cells, our understanding of the disease biology and treatment has improved. The development of a new class of agents, Bruton tyrosine kinase inhibitors (BTKi), has substantially impacted the treatment paradigm of WM. Herein, we review the current and emerging BTKi and the evidence for their use in WM. RECENT FINDINGS: Clinical trials have established the role of covalent BTKi in the treatment of WM. Their efficacy is compromised among patients who harbor CXCR4WHIM mutation or MYD88WT genotype. The development of BTKC481 mutation-mediated resistance to covalent BTKi may lead to disease refractoriness. Novel, non-covalent, next-generation BTKi are emerging, and preliminary results of the early phase clinical trials show promising activity in WM, even among patients refractory to a covalent BTKi. Covalent BTK inhibitors have demonstrated meaningful outcomes in treatment-naïve (TN) and relapsed refractory (R/R) WM, particularly among those harboring the MYD88L265P mutation. The next-generation BTKi demonstrate improved selectivity, resulting in a more favorable toxicity profile. In WM, BTKi are administered until progression or the development of intolerable toxicity. Consequently, the potential for acquired resistance, the emergence of cumulative toxicities, and treatment-related financial burden are critical challenges associated with the continuous therapy approach. By circumventing BTK C481 mutations that alter the binding site to covalent BTKi, the non-covalent BTKi serve as alternative agents in the event of acquired resistance. Head-to-head comparative trials with the conventional chemoimmunotherapies are lacking. The findings of the RAINBOW trial (NCT046152), comparing the dexamethasone, rituximab, and cyclophosphamide (DRC) regimen to the first-generation, ibrutinib are awaited, but more studies are needed to draw definitive conclusions on the comparative efficacy of chemoimmunotherapy and BTKi. Complete response is elusive with BTKi, and combination regimens to improve upon the efficacy and limit the treatment duration are also under evaluation in WM.
Assuntos
Tirosina Quinase da Agamaglobulinemia , Inibidores de Proteínas Quinases , Macroglobulinemia de Waldenstrom , Macroglobulinemia de Waldenstrom/tratamento farmacológico , Macroglobulinemia de Waldenstrom/genética , Humanos , Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Tirosina Quinase da Agamaglobulinemia/genética , Inibidores de Proteínas Quinases/uso terapêutico , Resultado do Tratamento , Mutação , Gerenciamento Clínico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversosRESUMO
The bendamustine-rituximab (BR) schedule is an efficient first-line therapy in Waldenström macroglobulinaemia (WM). A previous analysis of 69 patients who received this treatment confirmed a high response rate and good progression-free (PFS) and overall survival (OS). With a median follow-up of 76.1 months (95% confidence interval [CI] 69.9-80.6), 5-year outcome is still excellent at 66.63% (95% CI 56.09-79.17) for PFS and 80.01% (95% CI 70.82-90.41) for OS. The rate of secondary cancers is 17.66% (IQR 7.99-27.64) at 66 months. Relapsed patients who received ibrutinib as second-line clearly benefited from this schedule. This confirms current recommendations suggesting BR long-term efficacy as first-line option in WM.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Cloridrato de Bendamustina , Rituximab , Macroglobulinemia de Waldenstrom , Humanos , Cloridrato de Bendamustina/administração & dosagem , Cloridrato de Bendamustina/uso terapêutico , Macroglobulinemia de Waldenstrom/tratamento farmacológico , Macroglobulinemia de Waldenstrom/mortalidade , Rituximab/administração & dosagem , Rituximab/uso terapêutico , Masculino , Feminino , Idoso , Pessoa de Meia-Idade , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Idoso de 80 Anos ou mais , França , Seguimentos , Resultado do TratamentoRESUMO
ABSTRACT: The phase 3 ASPEN trial (NCT03053440) compared Bruton tyrosine kinase inhibitors (BTKis), zanubrutinib and ibrutinib, in patients with Waldenström macroglobulinemia (WM). Post-hoc biomarker analysis was performed using next-generation sequencing on pretreatment bone marrow samples from 98 patients treated with zanubrutinib and 92 patients treated with ibrutinib with mutated (MUT) MYD88 and 20 patients with wild-type (WT) MYD88 treated with zanubrutinib. Of 329 mutations in 52 genes, mutations in CXCR4 (25.7%), TP53 (24.8%), ARID1A (15.7%), and TERT (9.0%) were most common. TP53MUT, ARID1AMUT, and TERTMUT were associated with higher rates of CXCR4MUT (P < .05). Patients with CXCR4MUT (frameshift or nonsense [NS] mutations) had lower very good partial response (VGPR) and complete response rates (CR; 17.0% vs 37.2%, P = .020) and longer time to response (11.1 vs 8.4 months) than patients with CXCR4WT treated with BTKis. CXCR4NS was associated with inferior progression-free survival (PFS; hazard ratio [HR], 3.39; P = .017) in patients treated with ibrutinib but not in those treated with zanubrutinib (HR, 0.67; P = .598), but VGPR + CR rates were similar between treatment groups (14.3% vs 15.4%). Compared with ibrutinib, patients with CXCR4NS treated with zanubrutinib had a favorable major response rate (MRR; 85.7% vs 53.8%; P = .09) and PFS (HR, 0.30; P = .093). In patients with TP53MUT, significantly lower MRRs were observed for patients treated with ibrutinib (63.6% vs 85.7%; P = .04) but not for those treated with zanubrutinib (80.8% vs 81.9%; P = .978). In TP53MUT, compared with ibrutinib, patients treated with zanubrutinib had higher VGPR and CR (34.6% vs 13.6%; P < .05), numerically improved MRR (80.8% vs 63.6%; P = .11), and longer PFS (not reached vs 44.2 months; HR, 0.66; P = .37). Collectively, patients with WM with CXCR4MUT or TP53MUT had worse prognosis compared with patients with WT alleles, and zanubrutinib led to better clinical outcomes.
Assuntos
Adenina/análogos & derivados , Piperidinas , Pirazóis , Pirimidinas , Macroglobulinemia de Waldenstrom , Humanos , Macroglobulinemia de Waldenstrom/tratamento farmacológico , Macroglobulinemia de Waldenstrom/genética , Fator 88 de Diferenciação Mieloide/genética , BiomarcadoresRESUMO
There remains a lack of consensus as to the most appropriate primary therapy in Waldenstrom macroglobulinemia (WM). We evaluated a novel bortezomib-based combination and developed a sensitive WM-specific flow cytometry assay (limit of detection 0.004% of leucocytes) to assess bone marrow (BM) response. Sixty treatment-naïve WM patients were enroled into this phase II trial and randomised (2:1) to receive cyclophosphamide and rituximab with either bortezomib (BRC) or fludarabine (FCR). The primary objective was to assess the overall response rate (ORR) in eligible patients receiving BRC (N = 41). An ORR of 97.6% (95%CI:87.1-99.9) was observed; 27 (65.9%) patients remain alive without progression after 62.6 months median follow-up, with 2-, 3- and 5-year progression-free survival (PFS) rates of 92.7% (95%CI:79.0-97.6), 80.5% (95%CI:64.8-89.7) and 65.5% (95%CI:48.8-77.9). Persistent WM B-cells were demonstrable in 19/38 patients at the end of treatment (median 0.24%, range 0.02-11.2%). PFS was markedly longer in patients with BM B-cell depletion (<0.004%) compared to those who had persistent BM B-cells detectable at end of treatment (HR = 0.06, 95%CI:0.01-0.47, p < 0.001), and remained independently associated after adjusting for baseline risk stratification or investigator-assessed response. BRC is a tolerable, highly efficacious regimen for treatment-naïve WM patients. BM B-cell depletion is independently associated with patient outcomes.
Assuntos
Macroglobulinemia de Waldenstrom , Humanos , Rituximab/uso terapêutico , Macroglobulinemia de Waldenstrom/tratamento farmacológico , Macroglobulinemia de Waldenstrom/diagnóstico , Bortezomib/uso terapêutico , Medula Óssea , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ciclofosfamida/uso terapêuticoRESUMO
The treatment of Waldenström macroglobulinemia/lymphoplasmacytic lymphoma (WM/LPL) has evolved to include several new options. The NCCN Guidelines for WM/LPL provide a framework on which to base decisions regarding diagnosis, treatment, assessment of response to treatment, and follow-up of both newly diagnosed and previously treated WM/LPL.
Assuntos
Linfoma de Células B , Macroglobulinemia de Waldenstrom , Humanos , Macroglobulinemia de Waldenstrom/terapia , Macroglobulinemia de Waldenstrom/tratamento farmacológicoAssuntos
Adenina , Mutação , Fator 88 de Diferenciação Mieloide , Piperidinas , Macroglobulinemia de Waldenstrom , Macroglobulinemia de Waldenstrom/tratamento farmacológico , Macroglobulinemia de Waldenstrom/genética , Humanos , Fator 88 de Diferenciação Mieloide/genética , Piperidinas/uso terapêutico , Adenina/análogos & derivados , Adenina/uso terapêutico , Pirimidinas/uso terapêutico , Pirazóis/uso terapêutico , Pirazóis/farmacologia , Masculino , Resultado do Tratamento , Feminino , Prognóstico , MultiômicaRESUMO
ABSTRACT: Mutations in MYD88 (95%-97%) and CXCR4 (30%-40%) are common in Waldenström macroglobulinemia (WM). TP53 is altered in 20% to 30% of patients with WM, particularly those previously treated. Mutated MYD88 activates hematopoietic cell kinase that drives Bruton tyrosine kinase (BTK) prosurvival signaling. Both nonsense and frameshift CXCR4 mutations occur in WM. Nonsense variants show greater resistance to BTK inhibitors. Covalent BTK inhibitors (cBTKi) produce major responses in 70% to 80% of patients with WM. MYD88 and CXCR4 mutation status can affect time to major response, depth of response, and/or progression-free survival (PFS) in patients with WM treated with cBTKi. The cBTKi zanubrutinib shows greater response activity and/or improved PFS in patients with WM with wild-type MYD88, mutated CXCR4, or altered TP53. Risks for adverse events, including atrial fibrillation, bleeding diathesis, and neutropenia can differ based on which BTKi is used in WM. Intolerance is also common with cBTKi, and dose reduction or switchover to another cBTKi can be considered. For patients with acquired resistance to cBTKis, newer options include pirtobrutinib or venetoclax. Combinations of BTKis with chemoimmunotherapy, CXCR4, and BCL2 antagonists are discussed. Algorithms for positioning BTKis in treatment naïve or previously treated patients with WM, based on genomics, disease characteristics, and comorbidities, are presented.
Assuntos
Tirosina Quinase da Agamaglobulinemia , Inibidores de Proteínas Quinases , Macroglobulinemia de Waldenstrom , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Tirosina Quinase da Agamaglobulinemia/genética , Genômica/métodos , Mutação , Fator 88 de Diferenciação Mieloide/genética , Piperidinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/efeitos adversos , Pirazóis/uso terapêutico , Pirazóis/efeitos adversos , Pirimidinas/uso terapêutico , Receptores CXCR4/genética , Receptores CXCR4/antagonistas & inibidores , Macroglobulinemia de Waldenstrom/tratamento farmacológico , Macroglobulinemia de Waldenstrom/genéticaAssuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Bortezomib , Ciclofosfamida , Dexametasona , Rituximab , Macroglobulinemia de Waldenstrom , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bortezomib/administração & dosagem , Bortezomib/uso terapêutico , Ciclofosfamida/administração & dosagem , Ciclofosfamida/uso terapêutico , Dexametasona/administração & dosagem , Rituximab/administração & dosagem , Rituximab/uso terapêutico , Resultado do Tratamento , Macroglobulinemia de Waldenstrom/tratamento farmacológico , Macroglobulinemia de Waldenstrom/diagnóstico , AdultoRESUMO
This phase II study evaluated time-limited (24 cycles) treatment with ibrutinib and ixazomib in newly diagnosed (NDWM; n = 9) and relapsed/refractory (RRWM; n = 12) Waldenström macroglobulinaemia (WM). The overall response rate (ORR) was 76.2% (n = 16) in 21 evaluable patients with no patient achieving a complete response (CR). The median duration of treatment was 15.6 months, and after a median follow-up time of 25.7 months, the median progression-free survival (PFS) was 22.9 months. While the primary end-point was not met (CR rate at any time) and 28.5% discontinued treatment due to toxicity, ibrutinib plus ixazomib led to a clinically meaningful ORR and PFS. Combined Bruton's tyrosine kinase (BTK) and proteasome inhibition merits further evaluation in WM.
Assuntos
Adenina , Protocolos de Quimioterapia Combinada Antineoplásica , Compostos de Boro , Glicina , Piperidinas , Macroglobulinemia de Waldenstrom , Humanos , Compostos de Boro/uso terapêutico , Compostos de Boro/administração & dosagem , Compostos de Boro/efeitos adversos , Macroglobulinemia de Waldenstrom/tratamento farmacológico , Glicina/análogos & derivados , Glicina/administração & dosagem , Glicina/efeitos adversos , Glicina/uso terapêutico , Adenina/análogos & derivados , Masculino , Idoso , Pessoa de Meia-Idade , Feminino , Piperidinas/uso terapêutico , Piperidinas/administração & dosagem , Piperidinas/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Idoso de 80 Anos ou mais , Pirimidinas/efeitos adversos , Pirimidinas/uso terapêutico , Pirimidinas/administração & dosagem , Pirazóis/uso terapêutico , Pirazóis/efeitos adversos , Pirazóis/administração & dosagem , Adulto , Resultado do TratamentoRESUMO
PURPOSE: Despite the recent success of Bruton's tyrosine kinase (BTK) inhibitors for the treatment of Waldenstrom macroglobulinemia (WM), their indefinite treatment duration ultimately tantamount to substantial financial and emotional burden. On the other hand, fixed duration of proteasome inhibitors (PI) have shown rapid and reasonable response in WM treatment. Despite the well-known synergism between PI and immunomodulatory drugs (IMiD), there is no trials evaluating such combination in WM. MATERIALS AND METHODS: Based on above, we designed this phase II study to investigate the efficacy and safety of 6 cycles of 28-day bortezomib-thalidomide-dexamethasone (VTD) regimen for treatment-naïve WM. RESULTS: A total of 15 patients were enrolled: major response rate was 64.3%, and overall response rate was 78.6%. During the median follow-up of 41 months, median progression-free survival (PFS) was 13 months and overall survival 40 months. For responders, median duration of response was 13 months and median PFS 19 months. The most common adverse event (AE) of any grade was constipation (57.1%). The most common grade ≥ 3 AE was anemia (21.4%). CONCLUSION: All in all, we hereby provide proof-of-concept that PI + IMiD may be an attractive backbone for fixed duration treatment. It should be noted that granting the same level of access to newer drugs globally is virtually impossible. Thus efforts to develop regimens using readily available drugs to yield similar or adequate treatment outcomes should not be disregarded. In this sense, we believe our study holds its place for its novelty and eloquently addresses achieving the daunting societal quest of health equity.